1. Field of the Invention
This invention is in the field of medicinal chemistry. In particular, the invention relates to novel substituted 2,3-benzodiazepin-4-ones. These analogs are antagonists of .alpha.-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) ionotropic receptors. Certain of these analogs are positive modulators of AMPA receptors. The invention also is directed to the use of these substituted 2,3-benzodiazepin-4-ones for the treatment of neuronal damage following global and focal ischemia, and for the treatment or prevention of neurodegenerative conditions, as anticonvulsants and as cognitive enhancers and for the treatment of schizophrenia and pain. The invention is also directed to the process for the preparation of the substituted 2,3-benzodiazepin-4-ones.
2. Related Background Art
Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed "ionotropic." This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonist N-methyl-aspartate (NMDA), .alpha.-amino-3-hydroxy-5-methyoisoxazole-4-propionic acid (AMPA), and kainic acid (KA). The second general type is the G-protein or second messenger-linked "metabotropic" excitatory amino acid receptor. This second type, when activated by the agonists quisqualate, ibotenate, or trans-1-aminocyclopentane-1,3-dicarboxylic acid, leads to enhanced phosphoinositide hydrolysis in the postsynaptic cell. Both types of receptors appear not only to mediate normal synaptic connections during development, but also changes in the efficiency of synaptic transmission throughout life. See Schoepp, Bockaert, and Sladeezek, Trends Pharm. Sci. 11: 508 (1990); McDonald and Johnson, Brain Res. Rev. 15: 41 (1990). The excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity. The medical consequences of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal. See U.S. Pat. No. 5,284,957.
Antagonists of the AMPA receptor are considered useful in treating, preventing and ameliorating a number of neurologic disorders which are due to overstimulation by the excitatory amino acids. These include acute neurologic disorders such as domoic acid poisoning; cerebral ischemia, global ischemia associated with cardiac arrest; stroke; spinal cord trauma; hypoxia; anoxia; poisoning by carbon monoxide, manganese or cyanide; hypoglycemia; mechanical trauma to the nervous system, epileptic seizures; and chronic neurologic disorders such as Huntington's disease, neuronal injury associated with HIV and AIDS, AIDS dementia, neuropathic pain syndrome, olivopontocerebral atrophy, Parkinson's disease, amyotrophic lateral sclerosis, mitochondrial abnormalities, Alzheimer's disease, hepatic encephalopathy, Tourette's syndrome, schizophrenia, and drug addiction (see Lipton and Rosenberg, N. Engl. J. Med. 330: 613-622 (1994)).
Positive modulators of AMPA receptors are expected to be useful for the treatment or amelioration of a number of chronic neurologic disorders, such as schizophrenia, Alzheimer's disease and malnutrition and neural maldevelopment (Thomas, R. J., J. Am. Geriatr. Soc. 43: 1279-1289 (1995)). It has been shown that the AMPA receptor positive modulator BDP 1-(1,3-benzodioxol-5-ylcarbonyl) piperidine and its derivatives enhance memory (Staubli et al., Proc. Natl. Acad. Sci. 91: 777-778 (1994)). The AMPA positive modulator BDP-29 has been shown to attenuate the amount of stereotypic rearings seen in rats after methamphetamine injection, suggesting that AMPA receptor modulators might be useful for the treatment of schizopherenia (Larson et al., Brain Res. 738, 353-356 (1996)).
Recent studies have shown that AMPA receptor antagonists are neuroprotective in focal and global ischemia models. The competitive AMPA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzof!quinoxaline) has been reported to be effective in preventing global and focal ischemic damage. See Sheardown et al., Science 247: 571 (1990); Buchan et al., Neuroreport. 2:473 (1991); Lepeillet et al., Brain Res. 571:115 (1992). The noncompetitive AMPA receptor antagonist GKYI 52466 (1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine-hydro chloride) has been shown to be an effective neuroprotective agent in rat global ischemia models. See Lapeillet et al., Brain Res. 571: 115 (1992). GYKI 52466 has also been shown to be an effective anticonvulsant. See DeSarro et al., Eur. J. Pharmacol. 294: 411 (1995). These studies strongly suggest that the delayed neuronal degeneration in brain ischemia involves glutamate excitotoxicity mediated at least in part by AMPA receptor activation. Thus, AMPA receptor antagonists are expected to prove useful as neuroprotective agents and improve the neurological outcome of cerebral ischemia in animals. See U.S. Pat. No. 5,284,957.
Anderson et. af., J. Am. Chem. Soc. 117. 12358-12359 (1995) reported the synthesis of 5-H-2,3-benzodiazepine (LY300164) shown below. The compound is said to be a noncompetitive antagonist of AMPA receptors with anticonvulsant activity. ##STR1##
U.S. Pat. No. 4,614,740 discloses 2,3-benzodiazepines with general formula: ##STR2## wherein R and R.sub.1 each represent hydrogen, chlorine, C.sub.1-4 alkyl or C.sub.1-4 alkoxy, R.sub.2 stands for hydrogen or C.sub.1-4 alkyl, R.sub.3 and R.sub.4 each denote C.sub.1-4 alkyl, or combined they denote methylene. These compounds are said to possess valuable central nervous effect and in particular exert antiaggressive, anxiolytic, narcosis potentiating and soporific properties.
U.S. Pat. No. 4,835,152 discloses the preparation of 2,3-benzodiazepine: ##STR3## This compound is said to possess CNS stimulating activity.
EP patent application 0492485 discloses 2,3-benzodiazepines with the following formula: ##STR4## wherein R stands for a C.sub.1-6 aliphatic acyl group, optionally substituted by a methoxy, cyano, carboxyl amino, C.sub.1-4 alkylamino, di(C.sub.1-4 alkyl)amino, pyrrolidino, phthalimido or phenyl, or by one or more halogens, or R is a benzoyl, cyclopropanecarbonyl, C.sub.1-5 alkylcarbamoyl or phenylcarbamoyl, or R is absent when a double bond exists between the N(3) and C(4) atoms; R.sub.1 is hydrogen or absent when a double bond exists between the N(3) and C(4) atoms; R.sub.2 is a C.sub.1-3 alkyl group or R.sub.1 and R.sub.2 together stand for a methylene group and no double bond is present between the N(3) and C(4) atoms; R.sub.3 is hydrogen or a C.sub.1-4 aliphatic acyl group; R.sub.4 is hydrogen, a C.sub.1-6 aliphatic acyl group optionally substituted by a methoxy, cyano, carboxy, amino, C.sub.1-4 alkylamino, di(C.sub.1-4 alkyl)amino, pyrrolidino, phthalimido or phenyl group or by one or more halogen; as well as a benzoyl, palmitoyl, cyclopropanecarbonyl, C.sub.1-5 alkylcarbamoyl or phenylcarbamoyl group. These compounds are said to possess valuable central nervous system effects, particularly muscle-relaxant, anticonvulsive and neuroprotective action.
Sarro et al, Eur. J. Pharmacol., 294. 411-422 (1995) discloses the following 2,3-benzodiazepines (a-d) ##STR5## These compounds are said to be anticonvulsant agents in DBA/2 mice.